Treatment Efficacy and Molecular Dynamics of Neoadjuvant Durvalumab and Olaparib in Resectable Urothelial Bladder Cancer: The NEODURVARIB Trial

Abstract

Purpose: Neoadjuvant treatment of bladder cancer is evolving, with immunotherapy demonstrating promising activity. PARP inhibition combined with immune activation has been proposed as a synergistic strategy. We conducted a comprehensive molecular characterization of tumors treated with this combination in the neoadjuvant setting to provide crucial results for rational development.

Patients and methods: A phase II clinical trial was designed to evaluate the combination of anti-PDL1 inhibitor durvalumab and PARP inhibitor olaparib, focusing on biomarker dynamics in both pre- and post-treatment settings. A total of 29 patients were enrolled. Genomic and transcriptomic profiling, as well as analyses of immune cell populations, was conducted at baseline and at the time of cystectomy.

Results: Of the 29 patients treated, a pathologic complete response was observed in 13 cases (44.8%). No major safety concerns were associated with the treatment, and 26 patients (90%) underwent cystectomy. Mutational patterns, tumor mutation burden, and homologous recombination deficiency remained stable throughout treatment and were not predictive of outcomes. However, a shift toward stromal phenotypes and increased expression of epithelial-mesenchymal transition signatures were observed following therapy, particularly in resistant tumors. Moreover, an increase in circulating CD4+ CD27- CD28- T cells was noted among responders.

Conclusions: The combination of neoadjuvant durvalumab and olaparib shows therapeutic activity in bladder cancer. Resistance mechanisms seem to be driven by transcriptional adaptations rather than the emergence of new mutations.

Figure 1.

IHC profiling of samples under study. A, IHC patterns at baseline TURBT compared with cystectomy (CYST). PDL1 staining was assessed as the CPS but also in tumor cells (tumor) and immune cells separately (noted as “PDL1 tumor” and “PDL1 immune,” respectively). Mann–Whitney U test. B, Comparison of the median CPS between tumors with a squamous component (SCC) and pure urothelial cancers (Mann–Whitney U test) and sectorial graph depicting the response to treatment (blue: pCR; orange: progressive disease). Numbers represent the CPS. C, Percentage of patients who achieved a clinical response (green bars) vs. those who did not (red bars), classified by the positive or negative expression of different IHC markers in the baseline (TURBT) sample [PDL1, PDL1 in tumor cells, PDL1 in immune cells, FAP, CD8, CD4, FOXP3, and granzyme B (GZMB); Fisher t test]. NR, nonresponder; R, responder. Degrees of statistical significance: ns, nonsignificant; *, P < 0.05; **, P < 0.01.

Figure 2.

Genomic profiling comparing TURBT vs. cystectomies. A, Box and whisker plot showing the ratio of the allelic frequency of genetic variants in cystectomy samples between the allelic frequency in TURBT samples in responder vs. nonresponder patients (***, P < 0.001). B, Dot plot showing the fraction of mutations detected by WES that are coincident between the cystectomy and TURBT in responders and nonresponders (***, P < 0.001). C, Genetic variants detected in our cohort for the 29 most frequently mutated genes according to TCGA in the TURBT and cystectomy samples of responders (marked in green) and nonresponders (marked in red). D, Box and whisker plot comparing the TMB in samples from TURBTs vs. cystectomies. E, Comparison of the percentage of samples with genomic alterations related to HRDs (LOH, TAIs, LSTs, and HRD score) in TURBT samples vs. cystectomies and in responders vs. nonresponders comparing diagnostic samples and cystectomies. CYST, cystectomy. Degrees of statistical significance: ns, nonsignificant.

Figure 3.

Functionally enriched categories in transcriptomic studies for the comparisons of interest [baseline samples (TURBT) vs. cystectomies or nonresponders vs. responders]. A and B, Enriched categories for the Hallmark gene sets (Human MSigDB Collections—GSEA) in samples from cystectomies (posttreatment) vs. TURBTs (baseline). A, Enriched categories for the Hallmark gene sets (Human MSigDB Collections—GSEA) in nonresponders compared with responders (B). C, Enriched categories for the gene set corresponding to human chromosome cytogenetic bands (Human MSigDB Collections—GSEA) in the comparison of nonresponders compared with responders. Yellow bars indicate categories enriched in the study group, whereas blue bars indicate categories enriched in the control group, with a statistical significance of FDR < 0.25 (A) or <0.025 (B and C), respectively. The dashed vertical line reflects an FDR value of <0.001. The GSEA curves for the most significantly enriched categories are shown to the right of the bar graphs.

Figure 4.

Analysis of the data obtained from the transcriptomic profiling of the study samples. A, Volcano plots showing the transcriptionally deregulated genes in the comparisons of interest, whether comparing cystectomy (posttreatment) samples vs. TURBT (baseline) samples (left) or by response degree (nonresponder vs. responder, right). The horizontal axis shows the log₂ of the fold change, with the vertical dashed lines marking values below −2 or above +2. The vertical axis reflects the −log₁₀ of the P value, with the dashed line indicating an FDR value of <0.05. The top left and right quadrants indicate the genes with the greatest changes in fold change and statistical significance. Red circles represent overexpressed genes in the study condition (cystectomy in the left volcano plot and nonresponders in the right volcano plot), whereas blue circles represent overexpressed genes in the control condition (TURBT in the left volcano plot and responders in the right volcano plot). B, Panel indicating the molecular subtypes by which the study samples are classified based on their transcriptomic profile. The results shown in this panel were obtained using the in silico tool “BLCAsubtyping,” allowing their assignment to the various molecular groups previously described and discussed in Kamoun and colleagues (25), which includes classifications from the Baylor College of Medicine (Baylor), University of North Carolina (UNC), MD Anderson Cancer Center (MDA), Lund University (Lund), TCGA consortium, and Kamoun and colleagues’ own study (CIT-Curie, MIBC). Additionally, the mutational status of TP53, genes related to HR, and FGFR3 are reflected, along with the sample type [cystectomy (CYST) or TURBT] and patient response grade (green boxes, responders; red boxes, nonresponders). GU, genomically unstable; MES, mesenchymal; Sc/NE, small cell/neuroendocrine-like; URO, urothelial-like.